Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy

Lutz, Katie; Holte, Lenore; Kliethermes, Stephanie; Stephan, Carrie M.; Mathews, Katherine D.

doi:10.1212/wnl.0b013e3182a84140

Cited by 60 publications

(60 citation statements)

References 5 publications

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“…4 Patients with the smallest number of repeats demonstrate a more severe phenotype, including earlier wheelchair use and increased frequency of extramuscular manifestations (retinal vasculopathy and hearing loss). [5][6][7] A number of articles have looked at the relationship of D4Z4 methylation levels to penetrance of disease expression, with decreased methylation in patients expressing disease. 8,9 A linear relationship exists between the number of residual D4Z4 repeats and estimates of methylation in the D4Z4 region.…”

Section: Discussionmentioning

confidence: 99%

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

et al. 2015

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Objective: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort.Methods: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 5 normal, 12 5 severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use.Results: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p 5 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p 5 0.04); had age-adjusted clinical severity 39.8 points lower (p 5 0.004); had muscle pathology grades that were 2.4 points less severe (p , 0.0001); had quantitative myometry 28.3% predicted of normal higher (p 5 0.002); had global manual muscle testing scores 0.6 higher (p 5 0.005); and did not require wheelchairs. Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy due in its most prevalent form (FSHD1) to deletions in the D4Z4 macrosatellite repeat region on chromosome 4q35.1,2 While normal individuals have .10 repeats, patients with FSHD1 have between 1 and 10 repeats. The current model for disease proposes FSHD is an epigenetic disease: deletions lead to decreased CpG methylation and opening of chromatin structure. 3The open chromatin structure in combination with a polyadenylation signal polymorphism allow the transcription of a normally repressed gene located within the D4Z4 repeat, DUX4, which causes disease by a toxic gain of function. 4Patients with the smallest number of repeats demonstrate a more severe phenotype, including earlier wheelchair use and increased frequency of extramuscular manifestations (retinal vasculopathy and hearing loss).5-7 A number of articles have looked at the relationship of D4Z4 methylation levels to penetrance of disease expression, with decreased methylation in patients expressing disease. 8,9 A linear relationship exists between the number of residual D4Z4 repeats and estimates of methylation in the D4Z4 region.9 So for most patients with FSHD1, the repeat contraction is sufficient to decrease methylation and cause disease. Symptomatically affected patients with 7-10 repeats, unlike patients with 1-6 repeats, have divergent methylation values

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Section: Discussionmentioning

confidence: 99%

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

et al. 2015

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“…Dlatego u najmłodszych pacjentów zalecana jest systematyczna diagnostyka audiologiczna min. do ukończenia 6. roku życia [5]. U dorosłych 4 k. aragon-Gawińska, a. potulska-chromik, a.kostera-pruszczyk child neurology r e V i e w p a p e r w klasycznej postaci FSHD występowanie niedosłuchu może nie być częstsze niż w populacji ogólnej [6].…”

Section: Objawy Kliniczneunclassified

Facio-scapulo-humeral dystrophy (FSHD) – the latest update

2016

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StreSzczenieDystrofia twarzowo-łopatkowo-ramieniowa (FSHD) to trzecia co do częstości występowania dystrofia mięśniowa, dziedziczona autosomalnie dominująco. Pierwsze objawy zazwyczaj manifestują się w drugiej dekadzie życia, a bardzo wczesny początek (u dzieci przed 10. rokiem życia) wiąże się z ciężkim przebiegiem choroby, szybszym postępem niesprawności oraz większym ryzykiem powikłań. Praca ma na celu przedstawienie najważniejszych zagadnień dotyczących FSHD z punktu widzenia praktyki klinicznej -objawów, diagnostyki oraz opcji terapeutycznych, z uwzględnieniem wyników najnowszych badań, aktualnego piśmiennictwa oraz wytycznych opublikowanych przez Amerykańskie Towarzystwo Neurologiczne w 2015 roku. Słowa kluczowe: dystrofia twarzowo-łopatkowo-ramieniowa, niedosłuch, teleangiektazje siatkówkowe, niewydolność oddechowa, blok odnogi pęczka Hisa abStract Facio-scapulo-humeral dystrophy (FSHD) is a third most common muscular dystrophy of autosominal dominant pattern of inheritance. The onset of symptoms usually takes place in the second decade of life, whereas very early disease manifestation (in children below 10-year old) is linked to more severe clinical picture with quicker disability progression and higher risk of complications. This paper aims to present the most relevant issues in clinical practice concerning FSHD -symptoms, diagnostic process and therapeutic options, based on the latest publications, including evidence-based guidelines published by AAN in 2015.

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“…9,13,14 High frequency hearing loss is reported in approximately half of FSHD patients; however symptomatic hearing loss resulting in the need for hearing aids is almost exclusively seen in patients with the largest D4Z4 deletions. 8,15 A more severe infantile form of FSHD has been described. 16,17 These patients typically:…”

Section: Clinical Findingsmentioning

confidence: 99%

“…2,7 FSHD1 patients with the largest contractions are more likely to have extramuscular manifestations of FSHD, which include symptomatic retinal vascular disease and hearing loss. 8,9 The elucidation of a proposed common molecular mechanism behind both FSHD types 1 and 2 has opened the door to research in potential disease-directed therapies.…”

Section: Introductionmentioning

confidence: 99%

Facioscapulohumeral muscular dystrophy

Statland

Tawil

2011

Current Opinion in Neurology

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Facioscapulohumeral muscular dystrophy (FSHSD) is one of the most common adult muscular dystrophies and is divided into types 1 and 2 based on genetic mutation. Clinically both FSHD types 1 and 2 demonstrate often asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms, followed by the distal and then proximal lower extremities later in the disease course. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both FSHD types 1 and 2 share a common downstream mechanism making it possible that future disease-directed therapies will be effective for both FSHD types 1 and 2.

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Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy

Abstract: FSHD with a small EcoRI/BlnI fragment is associated with a bilateral, progressive, sloping, high-frequency hearing loss with onset in childhood. Patients with FSHD and small EcoRI/BlnI fragment sizes should have hearing screened, even if the child passed newborn hearing screening.

Cited by 60 publications

References 5 publications

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

Facio-scapulo-humeral dystrophy (FSHD) – the latest update

Facioscapulohumeral muscular dystrophy

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